Inhibitors of dipeptidyl peptidase 4 (DPP4) represent a novel class of antidiabetic drugs for treatment of type 2 diabetes. Because DPP4 inhibitors afford sustained reductions in HbA1c with a low risk of hypoglycemia and little effect on body weight, DPP4 inhibitors are widely employed to manage the world-wide pandemic of type 2 diabetes. For example, the DPP4 inhibitor sitagliptin is among the top 10 prescribed drugs in the USA (>100 million prescriptions per year) and is the 2nd leading branded oral antidiabetic agent in the USA. Alarmingly, evidence is accumulating that chronic DPP4 inhibition increases heart failure risk in type 2 diabetic patients. However, due to a complete lack of a theoretical model that could explain the biochemical basis of this clinical finding and due to the absence of an adequate animal model to recapitulate the clinical results, the mechanism of the increased heart failure risk in patients taking DPP4 inhibition remains unknown. Therefore, at present we do not know how or why DPP4 inhibitors cause adverse cardiac effects, which patients are at risk or how to prevent the risks of DPP4 inhibitors while sustaining the benefits. The overarching goal of this application is to remedy this situation. In this application, we propose a comprehensive model for how DPP4 inhibitors cause cardiac (and renal) fibrosis. Previously, we discovered that full-length neuropeptide Y and peptide YY [NPY(1-36) and PYY(1-36), respectively] exert pro-growth effects (i.e., cell proliferation and extracellular matrix production) on cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), glomerular mesangial cells (GMCs). We also found that DPP4 inhibition augments the pro-growth effects of NPY(1-36) and PYY(1-36) because DPP4 normally inactivates NPY(1-36) and PYY(1-36) by removing two N-terminal amino acids. Recently, we performed preliminary studies to determine whether DPP4 substrates other than NPY(1- 36) and PYY(1-36) could also affect proliferation of, and extracellular matrix production by, CFs, PGVSMCs and GMCs and whether DPP4 inhibition augments the effects of these peptides. Our preliminary data suggest that CXCL12(1-68) may indeed activate CFs, PGVSMCs and GMCs. Moreover, these effects of CXCL12(1- 68) appear to be augmented by DPP4 inhibition and synergize with NPY(1-36) and PYY(1-36). This makes sense because CXCL12(1-68) is an excellent substrate for DPP4 and is metabolized by DPP4 to CXCL12(3- 68). CXCL12(1-68) is a potent agonist at CXCR4 receptors, while CXCL12(3-68) is not. Herein we propose (and describe experiments to test) the model that chronic DPP4 inhibition results in cardiac, and perhaps renal, fibrosis by blocking the metabolism of NPY(1-36), PYY(1-36) and CXCL12(1-68). Moreover, we propose, and have evidence supporting, the concept that insulin degrading enzyme (IDE) inhibitors (under development for type 2 diabetes) synergize with DPP4 inhibitors to worsen organ fibrosis. We will test our hypothesis in a comprehensive set of vertically-integrated (in vitro to in vivo) experiments.